Imaging drug transport in the brain
Drug resistance is a significant clinical problem, particularly in central nervous system (CNS) diseases. While some 50 million people worldwide have epilepsy, current treatments are ineffective for 30 % of patients. One possible explanation for this drug resistance is that non-specific transporter systems reduce drug concentrations within the brain to below therapeutic levels. Multidrug transporters like the P-glycoprotein (P-gp) and breast cancer resistance protein, thus lower the efficacy of certain lipophilic drugs that treat cancer, epilepsy and HIV. To develop inhibitors of P-gp transporters, the EU-funded EURIPIDES project aimed to develop radiotracers to image P-gp function and distribution. To validate the radiotracers that act as biomarkers of P-gp function, studies were carried out on relevant groups of patients with CNS diseases. Comparative studies were carried out to identify patients who are responsive or refractory to medicines. A comprehensive study of P-gp inhibitor–based positive emission tomography (PET) tracers resulted in three candidates being entered into human trials: laniquidar, tariquidar (TQD) and phenytoin. TQD trials produced the first direct evidence that P-gp transporters at the blood–brain barrier (BBB) are dysfunctional in sporadic Alzheimer's disease. This suggests that decreased P-gp function may be involved in the pathogenesis of this disease. In patients with temporal lobe epilepsy, drug-sensitive patients were found to have less efficient P-gp function than the drug-resistant patients. This suggests that more effective P-gp functioning results in faster clearance of drug in the patients’ brain reducing its efficacy. EURIPIDES has developed new PET and single-photon emission computed tomography tracers to assess adenosine triphosphate–binding cassette transporter function and expression in vivo. The findings provide evidence supporting the hypothesis of multidrug transporter over-expression contributing to pharmaco-resistance in epilepsy. One particularly exciting application is personalising treatment of epilepsy or cancer patients having raised P-gp function by using inhibitors such as TQD. These outcomes could also be extrapolated to treat BBB dysfunction seen in stroke patients, reduce disease severity in multiple sclerosis and treat some psychiatric disorders.
